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Primary Biliary Cirrhosis(PBC)
Thomas W. Faust, M.D., M.B.E.Associate Prof. of Clinical Medicine
The University of PennsylvaniaMay 19, 2010
PBCOverview
Introduction Epidemiology Genetics Pathogenesis Clinical presentation Extrahepatic
manifestations Differential diagnosis Diagnosis
Management– Medical– Surgical
Complications– Portal hypertension– Cholestasis
Natural history and prognosis
Summary
PBCIntroduction
Chronic cholestatic liver disease
Autoimmune basis Middle-aged females Disease of small bile
ducts– Cirrhosis with portal
hypertension– Complications of
cholestasis
Diagnosis– Liver function tests– Antimitochondrial
antibodies (AMA)– Histology
UDCA for all patients Transplantation
– Marginal liver reserve– Poor quality of life– Prognostic models
PBCEpidemiology
Female:male ratio of 9:1 Most common during middle age Presentation similar between genders,
races, and sexes Prevalence: 19-150 cases/million Incidence: 4-15 cases/million/yr Incidence/prevalence rates increasing? Familial clustering
Kaplan et al. NEJM 2005;353(12):1261
PBCGenetics
MHC class II– DR8, DQA1*0102, and DQ/1*0402
MHC class III– C4 null, and c4B2
Non-MHC genes– Exon 1 of CTLA-4
Increased familial risk – PBC/positive AMA and impaired T-cell regulation– Extrahepatic autoimmune diseases
PBCPathogenesis
A model autoimmune disease Genetic susceptibility plus triggering event AMA titer
– No correlation with disease severity– No difference in AMA (+) and (-) disease– Role in pathogenesis?– Reactive against E2 subunit of pyruvate dehydrogenase
Antigen expression– Inner mitochondrial membrane– Luminal surface of biliary epithelial cell– Interlobular and septal bile ducts
Apoptosis– Cholangiocyte Fas receptor expression
Cholestasis
James et al. Ann. Intern Med 1983;99(4):500Selmi et al. Gastroenterology 2004;127(2):485
PBCPathogenesis
Antigens on inner mitochondrial membrane– Oxoacid dehydrogenase complex– Autoreactivity to E2 subunit of this complex
Molecular mimicry– Bacterial or viral proteins, or halogenated
hydrocarbons similar to E2 subunit?– Immune attack of biliary epithelial cells
• CD4 and CD8 T lymphocytes• Aberrantly expressed antigens
– Antigens similar to E2 subunit exposed after contact with exogenous xenobiotics that damage biliary epithelial cells
– MHC class II and I antigen restriction and T cell interactions
Gershwin et al. Hepatology 2005;42(5):1194Selmi et al. Gastroenterology 2004;127(2):493Kaplan et al. NEJM 2005;353:1261
PBCAsymptomatic Disease
50-60% of patients (earlier diagnosis) 36-89% of asymptomatic patients develop symptoms
within 4.5-17 years Elevated AMA Liver biopsy C/W PBC Liver chemistry tests
– Normal– Cholestatic
50-70% 10 year survival in asymptomatic patients and median survival of 5-8 years from onset of symptoms (pre-UDCA era)
UDCA associated with better survival when compared to pre-UDCA era
Balasubramaniam et al. Gastroenterology 1990;98(6):1567
PBCSymptomatic Disease
Fatigue (common) Pruritus Jaundice Hepatosplenomegaly RUQ pain Hyperpigmentation
Xanthomas and xanthelasmas
Dyslipidemia Extrahepatic
autoimmune diseases Complications
– Portal hypertension– Chronic cholestasis
Koulentaki et al. Am J Gastroenterol 2006;101(3):541
PBCComplications
Chronic cholestasis– Osteopenia– Malabsorption– Steatorrhea
• Bile salt deficiency
• Pancreatic disease
• Celiac disease
– Vitamin A, D, E, K deficiency
Portal hypertension– Esophageal and
gastric varices– Ascites– Encephalopathy– SBP– HRS or HPS– Hepatocellular
carcinoma
PBCMetabolic Bone Disease
Osteoporosis– Most common– Duration/severity of
PBC and jaundice– Axial skeleton– Reduced osteoblastic
activity – DEXA scanning– Calcium, vitamin D,
and bisphosphonates?– Estrogens?
Osteomalacia– Less common– Vitamin D deficiency
and fat malabsorption– Calcium and
phosphate levels– 25-hydroxyvitamin D
level– Calcium and vitamin D
supplements
PBCDyslipidemia
Early disease– Increased HDL, LDL, and VLDL
Late disease– Fall in HDL and rise in LDL
Xanthomas and xanthelasmas– Cholesterol > 600 mg/dL
Atherosclerosis risk– No increased risk of ischemia heart disease, stroke
or TIA unless there is a separate lipid disorder
PBCAssociated Diseases
Thyroid disease– Hashimoto’s thyroiditis– Grave’s disease
Scleroderma CREST syndrome Sjogren’s syndrome Arthritis Raynaud’s
phenomenon Celiac disease
Renal tubular acidosis– Proximal
– Distal
Gallstones Hematologic disorders Inflammatory bowel
disease (rare) Pulmonary interstitial
fibrosis (rare)
PBCDifferential Diagnosis
Biliary stones or strictures
Pancreaticobiliary malignancies
PSC Autoimmune
hepatitis Alcoholic hepatitis
Viral hepatitis Sarcoidosis Autoimmune
cholangiopathy Medications Granulomatous
hepatitis
PBCNon-Invasive Tests
Biochemical tests– Alkaline phosphatase– GGT– 5’ nucleotidase– AST and ALT– Bilirubin– Total cholesterol– Serum IgM– Prothrombin time– Albumin
Serology– AMA (95%)– ANA (50%)– ASMA (50%)– Anti-centromere– Anti-thyroid
Medical imaging– Ultrasound– CT – MR or MRCP
Dickson et al. Hepatology 1989;10(1):1Muratori et al. Clin Liver Dis 2008;12(2):261Kaplan et al. N Engl J Med 2005;353(12):1261
PBCHistology
Stage I (portal)– Inflammation of
interlobular and septal bile ducts
– Granulomatous (florid duct) lesion
Stage II (periportal)– Inflammation of
interlobular and septal bile ducts
– Ductular proliferation
Stage III (septal)– Inflammation of
interlobular and septal bile ducts
– Fibrosis– Bile duct loss– Cholestasis
Stage IV (cirrhotic)– Established cirrhosis
Scheuer et al. Mayo Clin Proc 1998;73(2):179
PBCOverall Management
Survival of patients with PBC inferior to that of a healthy control population
Medical or surgical treatment warranted in all patients
No medical therapy has been shown to conclusively alter the history of PBC
Goals of treatment– Slow disease progression– Treat complications
PBCMedical Management
PBC: an autoimmune disease Improve clinical symptoms and signs
of disease Improve liver function tests Reduce or eliminate bile duct injury Improve patient survival free of
transplantation
PBCMedical Management
Ineffective– Corticosteroids– Azathioprine– Cyclosporine– Penicillamine– Colchicine– Chlorambucil
Possibly effective– Methotrexate– Mycophenolate mofetil
Effective – Ursodeoxycholic acid
• Improvement in symptoms
• Improvement in LFTs• Improvement in
histology• Improvement in
transplant free survival
Combination therapy?– Additional studies
warranted
PBCUDCA
Effective dose: 13-15 mg/kg/day indefinitely Mechanism of action
– Promotes endogenous bile acid secretion– Replacement of hepatotoxic (endogenous) bile acids– Stabilizes biliary epithelial cell membranes– Alters HLA I-II expression on biliary epithelial cell– Inhibits biliary cell apoptosis
Improvement in LFTs Delays disease progression and improves transplant-free
survival Follow LFTs every 3-6 mo.
Poupon et al. N Engl J Med. 1994;330(19):1342Heathcote et al. Hepatology 1994;19(5):1149
PBCIncomplete Responders to UDCA
66% of patients Definition
– Failure to normalize LFTs– Development of cirrhosis on therapy
Predictors of incomplete response– High alkaline phosphatase or GGT– Advanced disease prior to UDCA initiation
Assess: patient compliance, UDCA dose, overlap syndrome
Combes et al. Hepatology 1995;22(3):759Poupon et al. J Hepatolol 2003;39(1):12
PBCMethotrexate
Dose: 7.5-15 mg/week orally Improvement
– Symptoms– LFTs– Histology?– Survival?
Side effects limit long-term use
PBCCombination Therapies
UDCA and corticosteroids– Improvement in LFTs– Variable improvement in histology
UDCA and colchicine– No significant benefit
UDCA and methotrexate– Improvement in LFTs ?– Additional studies warranted
PBCNovel Agents
Malotilate– Improvement in LFTs– No improvement in survival
Bezafibrate– Improvement in LFTs
Thalidomide– No improvement in LFTs– No improvement in histology
PBCLiver Transplantation
Advanced PBC with marginal reserve
Portal hypertension– Refractory variceal
bleeding– Intractable ascites– Intractable
encephalopathy– SBP– HRS or HPS
Chronic cholestasis– Intractable pruritus – Metabolic bone
disease and fractures– Malabsorption– Vitamin deficiency
Hepatocellular Cancer Transplant options
– Cadaveric donation– Live donation
Lee et al. Clin Gastroenterol Hepatol 2007;5(11):1313Dickson et al. Hepatology 1989;10(1):1
PBCLiver Transplantation
Patient and graft survival– 1 yr : 83-92%– 5 yr : 75-85%
Higher risk of rejection PBC recurrence
– 15 to 25% of patients at 10 years– Granulomatous bile duct injury– AMA does not define recurrence– Exclude other post transplant disorders– Intermediate term patient and graft survival are good– Use of UDCA for recurrent disease uncertain
Liermann et al. Hepatology 2001;33(1):22
PBCComplications of Portal Hypertension
Variceal bleeding– Endoscopic screening– Non-selective beta
blockers– Endoscopic therapy
• Sclerotherapy• Band ligation
– Surgical shunts– TIPS
HCC– AFP/imaging
Ascites– Sodium restricted diets– Diuretics– Therapeutic
paracentesis– TIPS
Encephalopathy– Lactulose– Neomycin– Rifaxamin– Protein modification
PBC Metabolic Bone Disease
30-50% of patients Classification
– Osteoporosis: common– Osteomalacia: rare
Bone density– Below fracture
threshold (33%)
Diagnosis and F/U– DEXA scan– Every 1-2 yrs
Management– Calcium and vitamin D– Adequate exercise– Estrogen replacement
• Post menopausal
– Other medications• Alendronate• Etidronate
– Transplantation• Progressive disease
PBCTreatment of Metabolic Bone Disease
Calcium– 1000-1500 mg/d
Vitamin D– 800-1000 IU (normal 25-OH vitamin D level)– 50,000 IU vitamin D2, 2-3 times weekly if 25-OH
vitamin D level is low) then maintenance Bisphosphonates
– Alendronate 70 mg weekly– Data lacking regarding efficacy
Estrogens– Not first line because of complications
PBCPruritus
Antihistamines– 50% response rate
Cholestyramine– 90% response rate
Phenobarbital– Somewhat beneficial– Sedative side effects
UDCA– Inconsistent results
Rifampin– Rapid onset of action– Can cause liver injury
Other medications– Opiate antagonists– Sertraline– Ondansetron?
Other– Extracorporeal support– OLT
PBCVitamin Deficiency
Vitamin A– 20% of patients– Night blindness– Replace as appropriate– Can cause liver injury
Vitamin D– Replace as appropriate– Can cause liver injury– Supplemental calcium
Vitamin E– Rarely seen in adults
– Neurologic sequelae• Reduced proprioception• Ataxia
– Replace as appropriate
Vitamin K– Risk of hemorrhage
– Replace as appropriate
PBCHypercholesterolemia
Elevated cholesterol: 85% of patients Stage I or II disease: increased HDL
predominates Stage III or IV disease: increased LDL No increased risk for ischemic heart disease Lipid-lowering drugs not recommended unless
there is a separate lipid disorder Plasmapheresis for xanthomatous neuropathy
and symptomatic planar xanthomas
PBCSteatorrhea
Causes– Reduced bile delivery
to intestine– Coexisting pancreatic
insufficiency– Coexisting celiac
disease– Coexisting bacterial
overgrowth
Management– Reduced bile delivery
• Low fat diet• Medium chain
triglycerides
– Pancreatic disease• Pancreatic enzymes
– Celiac disease• Gluten-free diet
– Bacterial overgrowth• Antibiotics
PBCPreventive Care
Avoid excess ETOH, obesity, smoking Monitor thyroid function annually EGD every 1-3 years DEXA every 1-4 years Fat soluble vitamin assessment every 1-3
years depending upon liver function AFP and cross sectional imaging in
patients with cirrhosis
Lindor et al. Hepatology 2009;50(1):291
PBCNatural History and Prognosis
PBC progresses over 15-20 yrs Median survival
– Asymptomatic disease: 10-16 yrs
– Symptomatic disease: 7.5-10 yrs
– Bili. (8-10 mg/dL): 2 yrs
40-100% of asymptomatic patients develop symptoms within 2-4 yrs
PBCPrognostic Models
Benefits– Predicting survival without transplantation– Determining need for transplant evaluation– Assessing effectiveness of medical therapies
Mayo model– Age, total bilirubin, albumin, PT, and volume overload– Bilirubin: most important variable– Doesn’t take into account intercurrent events
• Variceal hemorrhage, liver cancer, quality of life
Dickson et al. Hepatology 1989;10(1):1Murtaugh et al. Hepatology 1994;20(1 Pt 1):126
PBCSummary
Important cause of chronic cholestatic liver disease
Middle-aged females predominate Immune pathogenesis favored Other autoimmune diseases frequently
coexist PBC progresses in most patients
PBCSummary
Complications of portal hypertension and chronic cholestasis associated with progressive disease
UDCA is standard medical therapy for all patients
Transplantation reserved for patients with marginal liver reserve and complications
Prognostic models predict disease severity and need for transplantation